[unreadable] Diabetes is a world-wide major cause of morbidity and mortality associated with impaired glucose tolerance, obesity, hyperlipidemia, hypertension, and atherosclerosis. The absorption, production, uptake, and metabolism of glucose are regulated by insulin. Normal glucose homeostasis requires that insulin is properly synthesized and secreted from the (cell upon periodic increases in blood glucose. Diabetes is associated with disturbances in pancreatic (cell function that result in the loss of glucose-stimulated insulin secretion. Recent studies demonstrated an association between (cell function, proliferation, and/or survival with an intracellular signaling pathway termed the unfolded protein response (UPR). Upon accumulation of unfolded proteins in the lumen of the endoplasmic reticulum, signal transduction pathways are activated to increase the protein folding capacity and increase the protein degradative machinery. In addition, protein synthesis is transiently attenuated through PERK-mediated phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2(). Recently, we discovered that these signaling pathways also play a role in the ability for the (cell to respond to elevated blood glucose by upregulation of insulin production and secretion. We propose that (cells utilize the UPR to detect blood glucose and regulate insulin production so that defects and/or allelic polymorphisms in this signaling pathway may contribute to the progression of diabetes. The experiments proposed will test the hypothesis that glucose homeostasis is maintained by UPR-mediated regulation of insulin production in (cells, gluconeogenesis by the liver, and/or glucose utilization in peripheral tissues. Modern molecular genetics has provided new tools for the identification and analysis of disease genes previously inaccessible to study. In this proposal we will use mouse genetics to ask fundamental questions about the regulation of glucose homeostasis in vivo that previously were not possible. These in vivo models have the potential for providing novel biologic insights into human disease and may also facilitate testing of new therapies. [unreadable] [unreadable] [unreadable]